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Temporal auto-regulation during PU.1 locus SubTAD formation (4C-seq)

ABSTRACT: Epigenetic control of gene expression occurs through discrete spatial chromosomal units called topologically associating domains (TADs), but the exact spatial requirements of most genes are unknown; this is of particular interest for genes involved in disease. We therefore applied high-resolution chromosomal conformation capture-sequencing to map the three-dimensional (3D) organization of the locus encoding the key myeloid transcription factor PU.1 in healthy monocytes and acute myeloid leukemia (AML) cells. We identified a dynamic ~75kb unit (SubTAD) as the genomic region in which spatial interactions between PU.1 gene regulatory elements occur during myeloid differentiation and are interrupted in AML. Within this SubTAD, initiating the spatial chromosomal interactions requires PU.1 auto-regulation and recruitment of the chromatin-adaptor protein LDB1 (LIM domain-binding protein 1). However, once formed, this SubTAD remains stable even when auto-regulation is impaired. Thus, our data support that PU.1 auto-regulation functions in a ‘hit-and-run’ manner, whereby it organizes chromosomal loops to create a transcriptionally active chromatin architecture.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110683 | GEO | 2018/10/15

REPOSITORIES: GEO

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Project description:Background: Strict control of PU.1, encoded by SPI1, is importmant for myeloid development, and inhibition of PU.1 expression and activity, even moderate, can lead to acute myeloid leukemia (AML). Much effort has focused on regulatory elements at the SPI1 locus on controlling PU.1. Discovery of circular RNAs (circRNAs), a novel class of noncoding regulators, has raised additional questions regarding their impacts on PU.1 and the development of AML. Methods: We used the pan-cancer circRNA compendium MiOncoCirc to investigate the existence and expression pattern of circSPI1s. We designed short hairpin RNAs (shRNAs) targeting the back-spliced site to silence circSPI1 and then performed CCK8 proliferation assay, flow cytometry analysis and Wright-Giemsa stain to explore the function of circSPI1. We performed RNA-sequencing with and without circSPI1 knockdown, western bloting and luciferase assay to explore the potential mechanisms. We utilized machine learning techniques and integrated bioinformatic analysis to evaluate the prognostic value of circSPI1 for AML, based on TCGA and BeatAML cohorts. Results: We found that circSPI1, the circular RNA derived from the SPI1 gene (encoding PU.1), was highly expressed in AML than that in normal counterparts. Functional experiements showed circSPI1 acted as an oncogene, as evidenced by the observation that circSPI1 knockdown induced myeloid differentiation and apoptosis of AML cells. This was different from the parental gene SPI1 that is generally low expressed in AML and functions as a tumor suppressor. Mechanistic investigations revealed that circSPI1 exerted multiple regulatory roles in AML progression. On one hand, circSPI1 contributed to the orchestrated differentiation of AML cells by antagonizing SPI1 expression. On the other hand, circSPI1 was involved in proliferation and apoptosis by interacting with microRNAs miR-1307-3p, miR-382-5p and miR-767-5p, which was uncoupled with SPI1. Finally, circSPI1-regulated genes were associated with the clinical outcome of AML patients, implicating the clinical significance of circSPI1 in AML. Conclusions: We demonstrate that highly expressed circSPI1 acts as an oncogene in AML, through both antognizing PU.1 expression and binding to microRNAs that is independent to PU.1. Our data provide new insight into complex SPI1 gene regulation now involving cicrSPI1 as well as the independent role of cicrRNA in AML.

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Temporal auto-regulation during PU.1 locus SubTAD formation (4C-seq)

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